JP2002513010A - Solid supported synthesis of sulfonated 2-oxopiperazine - Google Patents

Abstract

  (57) [Summary] The present invention includes a method of making 2-oxopiperazine and similar compounds using a solid support resin, the method comprising: (a) removing a protecting group from an N-protected amino acid ester of the resin (where a protecting group is present); ), (B) reacting the resulting unprotected resin ester with a sulfonyl chloride, (c) reacting the resulting intermediate with an N-protected amino alcohol, (d) reacting N derived from the amino alcohol By removing the N-protecting group and (e) cleaving the product from the resin and cyclizing it.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to methods for synthesizing sulfonated 2-oxopiperazines and similar compounds using a solid support resin to facilitate purification of intermediates, and to such compounds. Including libraries.

BACKGROUND OF THE INVENTION Many of the first combinatorial libraries have evolved around the well-documented solid-supported synthesis of peptides and amino acid resin ester conversion. As a result, several methods of hydantoin and diketopiperazine have been reported. a) Gordon, D .; W. And Steele, J .; Bioorg
. Med. Chem. Lett. , Vol. 5 (1995), p. 47, b) K
owalski, J .; And Lipton, M .; A. By Tetrahed
ron Lett. , Vol. 37 (1996), p. 5839, c) Scot
t, B. O. Siegmund, A .; C. Marlowe, C .; K. ; Pe
i, Y. And Spear, K .; L. Mol. Diversity, v
ol. 1 (1995), p. 125, d) Goodfellow, V .; S. L
Audeman, C.I. P. Gerrity, J .; I. Burcard, M .;
Strobel, E .; Zuzack, J .; S. And McLeod, D .; A
. Mol. Diversity, vol. 2 (1996), p. 97,
e) Fresno, M .; Alsina, J .; Royo, M .; ; Barany
, G .; And Alberticio, F .; Tetrahedron Le
tt. , Vol. 39 (1988), p. 2639. The latter class of compounds has a rigid scaffold and, with some limitations in solubility and metabolic stability, have proven to be effective screening tools.
There are few reports on the synthesis of piperazine and 2-oxopiperazine on solid supports. a) Goff, D .; A. And Zuckremann, R .; N
. Tetrahedron Lett. , Vol. 37 (1996),
p. 6247, b) Dankhardt, S .; M. Sherry, R .; N. And Krstenansky, J .; Tetrahedron Lett et al.
. vol. 36 (1995), p. 4923, c) Goff, D.E. A. By T
etrahedron Lett. vol. 39 (1998), p. See 1473.

SUMMARY OF THE INVENTION The present invention includes a method for producing a sulfonated 2-oxopiperazine compound described below using a solid support resin.

[0004]

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The method comprises: (a) N-protected α-amino acid ester of a solid support resin

[0006]

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The N-protecting group is removed starting with and the unprotected ester is then reacted with the sulfonyl chloride R ² —SO ₂ Cl to give the following compound

[0008]

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And (b) reacting the obtained compound with an N-protected α-amino alcohol B1NHCH (R ³ ) CH ₂ OH through a Mitsunobu reaction to obtain the following compound

[0010]

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And (c) removing the N-protecting group from the obtained compound and cyclizing the sulfonated 2-oxopiperazine from the resin.

[0012] The present invention also relates to the above α-amino acid ester, which is a β-amino acid ester (or longer chain), such that the final product is a similar 7-membered or 8-membered ring (or more) cyclic compound. And / or replacing the α-amino alcohol with a β-amino alcohol (or a longer chain similar alcohol). Further, in the above structural formula, R ³ may be combined with N from the amino alcohol (by elimination of H attached thereto) to form a fused ring product.

DETAILED DESCRIPTION OF THE INVENTION As used herein, unless otherwise specified, “alkyl” refers to a branched,
A straight or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted hydrocarbon. The term "alkyl" may be used alone or as a part of another term may be shortened to "alk" (eg, alkoxy, alkylacyl) (Alk
ylacyl)). Preferred straight chain alkyls have from 1 to about 20 carbon atoms, more preferably have 1 to about 6 carbon atoms, still more preferably have 1 to about 4 carbon atoms, and most preferably It is methyl or ethyl. Preferred cyclic and branched alkyls have 3 to about 20 carbon atoms, more preferably 3 to about 6 carbon atoms. Suitable cyclic alkyls have one hydrocarbon ring, but may be two or three or more fused hydrocarbon rings. Preferred alkyl is
Unsaturated with one to about three double or triple bonds, these are preferably monounsaturated with one double bond. More preferred alkyls are saturated. Suitable alkyl substituents include alkyl, aryl, aryloxy, alkoxy, alkyl or aryl esters. More preferred alkyls are unsubstituted.

As used herein, “heteroatom” means nitrogen, oxygen or sulfur.

As used herein, “alkylene” refers to a straight-chain alkyl group attached to the other end of the alkylene at both termini, and “heteroalkylene” refers to a group between carbon atoms or / and Means an alkylene having one or more heteroatoms at one or both of its terminals.

As used herein, unless otherwise specified, “aryl” refers to a substituted or unsubstituted aromatic hydrocarbon ring. The term “aryl” may be used alone or as part of another term (eg, aryloxy, arylacyl). Preferred aryls have from 6 to about 10 carbon atoms in the aromatic ring, for a total of from about 6 to about 20, preferably up to about 12 carbon atoms. Preferred aryl is phenyl or naphthyl, most preferably phenyl. Suitable substituents for aryl include alkyl, aryl, alkoxy, aryloxy, alkyl or aryl esters, halo, nitro, amino,
Examples include cyano, acyl, alkyl or arylacyl. More preferred aryls are unsubstituted.

As used herein, unless otherwise specified, “heterocycle” means a cyclic hydrocarbon chain having one or more heteroatoms in a hydrocarbon ring. The ring may be saturated, unsaturated, or aromatic. Preferred heterocycles have from 1 to about 6 heteroatoms, more preferably 1 or 2 or 3 heteroatoms, most preferably 1 heteroatom in the ring. Preferred heterocycles have from 3 to about 12, more preferably 3 to about 7, carbon atoms in addition to the heteroatoms in the ring, for a total of from 3 to about 12, in addition to the heteroatoms, more preferably It has from 3 to about 10 carbon atoms. Suitable heterocycles have one ring, but may be two or three or more fused hydrocarbon rings. Heterocycles are unsubstituted or substituted. Suitable heterocyclic substituents are the same as those for alkyl.

As used herein, unless otherwise specified, “heteroaryl” refers to an aromatic heterocycle. Preferred heteroaryls have 1 to about 6 heteroatoms in the ring, more preferably 1 or 2 or 3 heteroatoms, most preferably 1 heteroatom. Preferred heteroaryls have from 5 to about 12, more preferably 5 to about 9, carbon atoms in addition to the heteroatoms in the aromatic ring,
And 5 to about 20 in addition to the total heteroatoms, more preferably 5 to about 10
Has carbon atoms. Preferred heteroaryls have one ring, but may have more than one fused ring, at least one of the fused rings containing at least one heteroatom. Heteroaryl is unsubstituted or substituted. Preferred heteroaryl substituents are the same as those for aryl.

The present invention uses a solid support resin that can be linked to the carboxy moiety of an amino acid. Suitable resins for use in the present invention have a hydroxyalkylene linkage site. Particularly preferred is a Merrifield or Wang resin (e.g., a polystyrene-based Merrifield resin (100-200 mesh), 2% DV
B, catalog number 01-64-0104, Calbiochem-Novabi
ochem Corp. , San Diego, Calif.), Hydroxymethyl polystyrene resin, and the like.

[0020] N-protected amino acids are easily esterified to the resins described above. Alternatively, such resins are commercially available with the N-protected amino acid already esterified to the resin described above (eg, Boc-glycine-Merrifield resin, catalog number 04-12-2507, Calbiochem-Novabiochem). C
orp. Available from

N-protecting groups on the above amino acids are known and include t-butyloxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmo
c), most preferably Boc. "Bl" shown in the structural formula is
Shows an N-protecting group.

The method of the present invention begins with an N-protected amino acid ester of a solid support resin as shown below.

[0023]

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The N-protecting group is generally present on the amino acid ester of the resin. This is because an N-protecting group is required for partial esterification of the amino acid to the resin. In the present invention, it is necessary to first remove the N-protecting group, which may be achieved using any known method (if no N-protecting group is present, this operation can be omitted).

The unprotected amino acid ester of the obtained solid support resin is converted to sulfonyl chloride

[0026]

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To produce the compounds shown below.

[0028]

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This reaction is preferably carried out in a halogenated solvent (eg dichloromethane) under basic conditions (eg diisopropylamine).

In the above structural formula, R¹Are intermediates and end products that are stable to the process of the invention.
Any part that provides a composition. Suitable R¹As hydrogen, al
A kill, aryl, heterocycle, heteroaryl, alkyl or arylamine,
Alkyl or aryl esters are included. More preferred R¹Is hydrogen and 1
To alkyl having about 4 carbon atoms. The alkyl is preferably saturated
Linear, branched or unsubstituted, or one or more, preferably hydroxy,
Toxi, ethoxy, thio, methylthio, ethylthio, amino, methylamino,
Tylamino, dimethylamino, diethylamino, guanide, carboxy, carba
Moyl, phenyl, hydroxyphenyl, indolyl and imidazolyl
Substituting with one kind selected from the group consisting of More preferably, R ¹ Is the side chain of a natural amino acid.

In the above structural formula, R ² can be any moiety that provides an intermediate and a final product that is stable to the process of the present invention. Suitable R ² includes hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or arylamine,
Alkyl or aryl esters are preferred, with more preferred R ² being aryl and heterocycles.

In the above structural formula, n is an integer from 0 to about 5, preferably from 0 to about 3. More preferably, n is 0 or 1, most preferably 0.

In the next step of the present invention, 3 is an N-protected amino alcohol

[0034]

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And reacting with Mitsunobu to obtain the following compound

[0036]

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Generating a.

The Mitsunobu reaction is described in a) Hughes, D .; "The Mit
sunobu Reaction ",Organic Reactions, V
ol. 42, Paquette, L .; A. Edition; 1992, John Wil
eye & Sons, NY, pp. 335-656, b) Swaze, E .; E. FIG. , Tetrahedron Lett. , vol. 38 (1997), p. 864
3. Is disclosed.

In the above structural formula, R ³ can be any moiety that provides an intermediate and a final product that is stable to the process of the present invention. Suitable R ³ includes hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or arylamine,
Examples include alkyl or aryl acyl, alkyl or aryl esters, alkyl or aryl sulfonyl. More preferred R ³ is hydrogen and 1
To alkyl having about 4 carbon atoms. The alkyl is a saturated, linear or branched, unsubstituted or one or more, preferably hydroxy, methoxy,
Ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanide, carboxy, carbamoyl,
It is substituted with one moiety selected from the group consisting of phenyl, hydroxyphenyl, indolyl and imidazolyl. More preferably, R ³ is the side chain of a natural amino acid.

In the above formula, R ⁴ is an alkylene or heteroalkylene moiety. R ⁴ has from 3 to about 10 carbon atoms in addition to the heteroatom in the ring (incorporating R ⁴ ), preferably has 3 or 4 carbon atoms in addition to the heteroatom in the ring, Preferably the ring has 3 or 4 carbon atoms in addition to the heteroatoms and no heteroatoms (of course such a ring has at least one N as described in 8 ). Preferred R ⁴ is saturated and unsubstituted or hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino,
Methylamino, ethylamino, dimethylamino, diethylamino, carboxy,
And carbamoyl. The most preferred R ⁴ is n- propylene.

In the above structural formula, m is an integer from 1 to 5, preferably from 1 to about 3. More preferably, m is 1 or 2, and most preferably 1.

The next step in the method of the invention involves removing the N-protecting group from 5 or 8 by any known method (similar to the analogous procedure described above).

The next step in the process of the present invention is to cleave the product from the resin and cyclize it to give the product shown below.

[0044]

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Involves generating This cyclization / cleavage from the resin reaction is carried out at elevated temperatures in moderately polar solvents under acidic conditions.

Cleavage and cyclization are preferably achieved in a solution of acetic acid in 2-butanol. Cleavage and cyclization reactions are largely independent of the amino acid or aminoaldehyde used. The temperature required to maximize cleavage and cyclization is typically from about 25C to about 70C.

The method of the present invention is useful when producing compounds individually, or when producing compounds in a library format by separating or mixing the compounds. The synthesis of compound libraries of structural formulas 6 and / or 9 can be readily performed using a multiple cell procedure, such as a 96 plate format (eg, Robbins Block), where R ¹ , R ² and R Different compounds having different combinations of ³ or R ⁴ can be produced simultaneously in each cell. In addition, a library of a mixture of compounds of structural formulas 6 and / or 9 can be prepared by reacting a reagent that is a mixture rather than a single compound. Both types of libraries are useful for rapid screening of new compounds for pharmacological and other activities.

An exemplary method of the invention is described in the following scheme.

[0049]

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The Boc-amino acid bound to the glycine-Merrifield resin 10 via an ester bond is used as a starting material. Deprotection of the amino group forms sulfonamide 11 . Wash the resin with diluted acetic acid to remove any residual amine. A Mitsunobu reaction is performed using the Boc-protected amino alcohol 12 to give the alkylated product 13 . The alkylation is repeated one or more times to ensure completion of the reaction. Finally, the Boc group is removed and the 2-oxopiperazine 14 is cleaved from the resin (2M AcOH in 2-BuOH).

The following is a representative example of the synthesis of 2-oxopiperazine using Boc-prolinol and Boc-alaninol.

Boc-Ala-Merrifield resin ester (1.070 g, 0.74 mm
ol, 0.69 mmol / g, NovaBiochem) in dichloromethane (
Rinse several times with DCM). Then trifluoroacetic acid (95%; TFA / H _Two Treat with O) for 1 hour at room temperature. Wash resin several times with DCM
And then with a 5% solution of diisopropylethylamine (DIPEA) in DCM
Wash and then wash again with DCM. The suspended resin (about 5 mL of DCM) is added to D
IPEA (645 mg, 869 μL, 5 mmol) and 4-methoxybenzene
Treatment with sulfonyl chloride (762 mg, 3.7 mmol, 5 eq) gave 16
Shake vigorously over time, filter and wash (DCM, methanol, and
Acetic acid (1% in DCM) several times with DCM, several times with DCM and finally methanol
) And dried under vacuum at room temperature for 20 hours to give the tree shown below.
Fat esterFifteen(1.121 g, new load, 0.61 mmol / g)
You.

[0053]

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Resin ester 15 (200 mg, 0.122 mmol, 0.61 mmol / g
) With tetrahydrofuran (THF) several times. Triphenylphosphine (P
_{h 3 P) (0.37mmol, 97mg} , 3eq) and (S) -1- (t- butoxycarbonyl) -2-pyrrolidine methanol (N-Boc-L- prolinol) (0.37mmol, 75mg, 3eq) Was dissolved in THF (about 4 mL) and added to the reactor, followed by diisopropylazodicarboxylate (DIAD
) (0.37 mmol, 75 mg, 73 μL, 3 eq). The reaction mixture is shaken vigorously for 8 hours. The resin is washed several times with THF. The alkylation operation is then repeated one or more times.

The crude resin product from the previous step is washed several times with DCM and then treated with trifluoroacetic acid (95%; TFA / H ₂ O) for 1 hour at room temperature. . The resin was washed with DCM and methanol and finally 2M Ac
Suspend in OH / 2-BuOH, shake vigorously at 50 ° C. for 15 hours and filter. The resin is washed several times with DCM and methanol, and the filtrate is collected and evaporated. Evaporation of the oily residue with chloroform (to remove traces of acetic acid and butanol) gives the following 16 purified products.

[0056]

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Compound 17 is prepared using a similar method. Resin ester 15 (300mg
, 0.183 mmol, 0.61 mmol / g) in tetrahydrofuran (THF
) Rinse several times. Triphenylphosphine (Ph ₃ P) (0.56 mmol, 1
48 mg, 3 eq) and N-Boc-L-alaninol (0.56 mmol,
113 mg, 3 eq) was dissolved in THF (about 9 mL) and added to the reactor, followed by diisopropyl azodicarboxylate (DIAD) (0.56 mmol,
113 mg, 110 μL, 3 eq). The reaction mixture is shaken vigorously for 8 hours and filtered. The resin is washed several times with THF. The alkylation operation is repeated one or more times.

The crude resin product from the previous step is washed several times with DCM and then treated with trifluoroacetic acid (95%; TFA / H ₂ O) for 1 hour at room temperature. . The resin was washed with DCM and methanol and finally 2 M A
suspended in cOH / 2-BuOH and vigorously shaken at 70 ° C. for 48 hours,
Filter. The resin is washed several times with DCM and methanol, the filtrate is collected,
Put on the evaporator. The oily residue (to remove trace amounts of acetic acid and butanol) when applied to the evaporator with chloroform, purified product of 1 7 shown below is obtained.

[0059]

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Having described certain embodiments of the invention, it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit and scope of the invention. They are included in the claims herein, and all such variations are within the scope of the invention.

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] February 9, 2000 (200.2.9)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image [In the formula, R ¹ is hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl amines, aryl amines, alkyl esters or aryl esters,, R ² is hydrogen, alkyl, aryl, heterocyclic, heteroaryl , An alkylamine, an arylamine, an alkyl ester, or an aryl ester; R ³ is hydrogen, an alkyl, an aryl, a heterocycle, a heteroaryl, an alkylamine, an arylamine, an alkylacyl, an arylacyl, an alkylester,
R ⁴ is an alkylene or a heteroalkylene, n is an integer from 0 to about 5, m is an integer from 1 to about 5, Bl is an aryl ester, an alkylsulfonyl, or an arylsulfonyl. N-protecting group], the method comprises: (a) N-protected amino acid ester of a solid support resin

Embedded image Removing the N-protecting group B1 and replacing it with hydrogen to produce an unprotected amino acid ester of the solid support resin, or starting with such an unprotected resin ester; b) converting the unprotected resin ester from step (a) to sulfonyl chloride

Embedded image And react with the following compound

Embedded image And (c) converting 3 to an N-protected alcohol shown below.

Embedded image And react with the following compound

Embedded image (D) removing the N-protecting group from 5 or 8 ; and (e) cleaving the product from the resin and cyclizing it to 6 or 9. Features method.

Embedded image Wherein R ¹ , R ² , R ³ and R ⁴ are selected such that the compound is stable.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Clofenstein Scene Leeds United States 45140 Ohio, La Brande Gistor Hill Drive 11721 F-term (reference) 4C050 AA01 BB04 CC08 EE02 FF02 GG03 HH01

Claims (10)

[Claims] 1. A method for producing a compound having the following structural formula, comprising: Wherein R ¹ , R ² , R ^3, and R ⁴ are compounds 1 , 2 , 3 , 3 , 4 , 5 , 6 , 7 , 8, and 9 for performing the method. Selected to be sufficiently stable, n
Is an integer from 0 to 5, m is an integer from 1 to 5, and Bl is an N-protecting group.] The method comprises: (a) an N-protected amino acid ester of a solid support resin Removing the N-protecting group B1 and replacing it with hydrogen to produce an unprotected amino acid ester of the solid support resin, or starting with such an unprotected resin ester; b) converting the unprotected resin ester from step (a) to sulfonyl chloride And reacting with the following compound: And (c) converting 3 to an N-protected alcohol shown below: And reacting with the following compound: (D) removing the N-protecting group from 5 or 8 ; and (e) cleaving the product from the resin and cyclizing it to 6 or 9. Features method. 2. (a) R ¹ is selected from hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or arylamine, alkyl or aryl ester; (b) R ² is hydrogen, alkyl, aryl, (C) R ³ is hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or arylamine, alkyl or aryl ester, alkyl or aryl ester, selected from heterocycle, heteroaryl, alkyl or arylamine, alkyl or aryl ester. aryl acyl is selected from alkyl or arylsulfonyl, (d) R ⁴ is the method according to claim 1, characterized in that an alkylene or heteroalkylene. 3. The method according to claim 1, wherein n is 0 or 1, preferably 0, and m is 1 or 2, preferably 1. 4. The process according to claim 1, wherein in step (c), the amino alcohol has the structural formula 4 , and from step (e) a product having the structural formula 6 is produced. The method described in. 5. The process according to claim 1, wherein in step (c) the amino alcohol has the structural formula 7 , and from step (e) a product having the structural formula 9 is produced. The method described in. 6. (a) R ¹ is hydrogen or alkyl, said alkyl having 1 to 4 carbon atoms and being saturated, straight-chain or branched, unsubstituted or hydroxy, methoxy, Substituted with one moiety selected from the group consisting of ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanide, carboxy, carbamoyl, phenyl, hydroxyphenyl, indolyl, and imidazolyl (B) R ² is selected from hydrogen, alkyl, aryl and heterocycle; (c) R ³ is hydrogen or alkyl, wherein the alkyl has 1 to 4 carbon atoms Having and saturated, linear or branched, unsubstituted or hydroxy, methoxy, ethoxy, thio, methyl , Ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanide, carboxy, carbamoyl, phenyl, hydroxyphenyl, indolyl, and imidazolyl; (d) R ⁴ is a saturated alkylene of 3-4 carbon atoms, said alkylene, unsubstituted or hydroxy, methoxy, ethoxy, thio, methylthio,
The compound according to any one of claims 1 to 5, wherein the compound is substituted with one type of moiety selected from the group consisting of ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, and carbamoyl. The method described in Crab. 7. The method according to claim 1, wherein each N-protecting group is Boc or Fmoc.
7.) A method according to claim 1, wherein (a) and (d) are each preferably carried out in a TFA solution, and step (e) is preferably carried out in an acetic acid / 2-butanol solution. The described method. 8. The method according to claim 1, wherein the resin is hydroxymethyl polystyrene. 9. A library of compounds represented by one or both of the following structural formulas: Wherein R ¹ , R ² , R ³ and R ⁴ are selected such that the compound is stable; preferably, (a) R ¹ is hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl Or (b) R ² is selected from hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester, and (c) R ³ is selected from arylamine, alkyl or aryl ester, , Hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or arylamine, alkyl or aryl ester, alkyl or arylacyl, alkyl or arylsulfonyl, (d) R ⁴ is alkylene or heteroalkylene A library of compounds characterized by: Preferably, in structural formula 6, (a) n is 0 to 2, preferably 0, (b) m is 1 to 3, preferably 1, and (c) R ¹ Is hydrogen or alkyl, said alkyl having 1 to 4 carbon atoms and being saturated, linear or branched, unsubstituted or hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, (D) R ² There is selected from hydrogen, alkyl, aryl and heterocyclic, (e) R ³ is hydrogen or alkyl, four coal the alkyl from 1 Have atoms, and saturated, straight or branched, unsubstituted or hydroxy, methoxy,
Ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanide, carboxy, carbamoyl,
Phenyl, hydroxyphenyl, indolyl and imidazolyl substituted with one moiety selected from the group consisting of: (f) R ⁴ is a saturated alkylene having 3 to 4 carbon atoms, Is unsubstituted or hydroxy, methoxy, ethoxy, thio, methylthio,
Claims include all compounds substituted with one moiety selected from the group consisting of ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, and carbamoyl. 10. A library of compounds according to 9.